1. Field of the Invention
This invention relates to analogs of uracil nucleosides in the treatment of viral infections. More particularly, this invention relates to carbocyclic analogs of uracil nucleosides in which the pentose moiety of the nucleosides is replaced by a cyclopentane ring in the treatment of viral infections. This invention also relates to certain novel carbocyclic analogs of uracil nucleosides.
2. Description of the Prior Art
Uracil nucleosides and the phosphate derivatives (nucleotides) of these nucleosides are obligatory components of the biosynthesis of nucleic acids, of certain interconversions of pyrimidine nucleosides and nucleotides, and of other essential biochemical events. Structural analogs of uracil nucleosides may interfere with enzymatic processes that require uracil nucleosides and nucleotides. Because of the essential involvement of uracil nucleosides and nucleotides in vital biochemical processes, interference with their functions may be manifested as important biological activity. The best known examples of clinically useful, antiviral nucleosides are 5-iodo-2'-deoxyuridine (IdUrd), a uracil nucleoside, and 9-.beta.-D-arabinofuranosyladenine (Ara-A), a purine nucleoside. The antiviral activities, the clinical usefulness, and the disadvantages of IdUrd have been described in review articles such as "Recent Advances in Chemotherapy of Viral Diseases" by W. H. Prusoff in Pharmacological Reviews, volume 19, pages 209-250, 1967; "Purines and Pyrimidines" by F. M. Schabel, Jr., and J. A. Montgomery in Chemotherapy of Virus Diseases, The International Encyclopedia of Pharmacology and Therapeutics, volume 1, edited by D. J. Bauer, Pergamon Press, Oxford and New York, 1972; and "Antiviral Agents as Adjuncts in Cancer Chemotherapy" by W. M. Shannon and F. M. Schabel, Jr., in Pharmacology and Therapeutics, volume 11, pages 263-390, Pergamon Press, Oxford, Great Britain, 1980. Reviews of the antiviral activity of Ara-A include the latter review of Shannon and Schabel and "The Antiviral Activity of 9-.beta.-D-arabinofuranosyladenine (Ara-A)" by F. M. Schabel, Jr., in Chemotherapy, volume 13, pages 321-338, 1968.
The term "carbocyclic analog of a nucleoside" designates a compound that has the same chemical structure as the nucleoside except that the oxygen atom of the furanose moiety of the nucleoside is replaced by a methylene group in the carbocyclic analog; or, differently expressed, in the carbocyclic analog a cyclopentane ring replaces the tetrahydrofuran ring of the analogous nucleoside. Such nucleoside analogs were designated carbocyclic analogs of nucleosides by Shealy and Clayton, Journal of the American Chemical Society, volume 88, pages 3885-3887, 1966. The natural nucleosides and many of their true nucleoside analogs are subject to the action of enzymes (phosphorylases and hydrolases) that cleave the nucleosides to the pentose and pyrimidine (or purine) moieties. The biological effects of such true nucleoside analogs may be lessened by the action of these degradative enzymes. In contrast, carbocyclic analogs of nucleosides do not possess the glycosidic bond present in the true nucleosides and, therefore, are not subject to the action of these degradative enzymes. They may also be more selective in their biological actions.
Carbocyclic analogs of uracil nucleosides in which X of Formula I, below, is hydrogen or methyl have been previously described by Shealy and O'Dell, Journal of Heterocyclic Chemistry, volume 13, pages 1015-1020, 1041-1047 and 1353-1354, 1976; and by Shealy, O'Dell and Thorpe, Journal of Heterocyclic Chemistry, volume 18, pages 383-389, 1981. Certain carbocyclic analogs of cytosine nucleosides have also been synthesized and described and their antiviral activity revealed by Shealy and O'Dell in U.S. Pat. No. 4,177,238, Dec. 4, 1979; U.S. Pat. No. 4,232,154, Nov. 4, 1980; and Journal of Heterocyclic Chemistry, volume 17, pages 353-358, 1980. The two U.S. patents disclose that analogs in which X of Formula I, below, is hydrogen, lower alkyl or halogen may be used as intermediates in the preparation of the cytosine nucleoside analogs. These patents also disclose that the hydroxyl groups on such compounds may be reacted with an acylating agent. Murdock et al in Journal of the American Chemical Society, volume 84, pages 3758-3764 (1962) claimed the formula of the carbocyclic analog of thymidine, i.e., the formula: ##STR2## However, Shealy, O'Dell, and Thorpe, Journal of Heterocyclic Chemistry, Volume 18, pages 383-389, 1981, have shown that the compound claimed by Murdock is not the carbocylic analog of thymidine. None of these references disclose that the carbocyclic analogs of uracil nucleosides mentioned therein exhibit antiviral activity.